53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ.

Ghezraoui, Hind; Oliveira, Catarina; Becker, Jordan R; Bilham, Kirstin; Moralli, Daniela; Anzilotti, Consuelo; Fischer, Roman; Deobagkar-Lele, Mukta; Sanchiz-Calvo, Maria; Fueyo-Marcos, Elena; Bonham, Sarah; Kessler, Benedikt M; Rottenberg, Sven; Cornall, Richard J; Green, Catherine M; Chapman, J Ross (2018). 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature, 560(7716), pp. 122-127. Macmillan Journals Ltd. 10.1038/s41586-018-0362-1

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53BP1 governs a specialized, context-specific branch of the classical non-homologous end joining DNA double-strand break repair pathway. Mice lacking 53bp1 (also known as Trp53bp1) are immunodeficient owing to a complete loss of immunoglobulin class-switch recombination, and reduced fidelity of long-range V(D)J recombination. The 53BP1-dependent pathway is also responsible for pathological joining events at dysfunctional telomeres, and its unrestricted activity in Brca1-deficient cellular and tumour models causes genomic instability and oncogenesis. Cells that lack core non-homologous end joining proteins are profoundly radiosensitive, unlike 53BP1-deficient cells, which suggests that 53BP1 and its co-factors act on specific DNA substrates. Here we show that 53BP1 cooperates with its downstream effector protein REV7 to promote non-homologous end joining during class-switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. We identify shieldin-a four-subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2) and FLJ26957 (SHLD3)-as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and non-homologous end joining during class-switch recombination, and supports toxic non-homologous end joining in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the context specificity of the pathway.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

0028-0836

Publisher:

Macmillan Journals Ltd.

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

03 Jun 2019 09:41

Last Modified:

03 Jun 2019 09:41

Publisher DOI:

10.1038/s41586-018-0362-1

PubMed ID:

30046110

BORIS DOI:

10.7892/boris.127532

URI:

https://boris.unibe.ch/id/eprint/127532

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